Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 124

Table 6.1 Profile of first-generation AR antagonists.
Compound

AR Binding Ki (nM) AR Transactivation IC 50 (nM)

1 360 152

2 21 130

3 19 224

4 3 45000

5 1170 2860

6 16 20

BMS-949 40 41

BMS-305 8 10

BMS-511 14 44

7 3 23

8 5 18

BMS-641988 2 16

2-hydroxyflutamide 43 26

bicalutamide 37 173

imide portion of 3 generate significant interactions with any residues in the AR
LBD. This result was surprising since the known non-steroidal anti-androgens
contain an aryl amide functionality isosteric with the imide system of these
BMS AR antagonists. Perhaps the primary role of the imide system is to
constrain the bicyclic and aromatic sections of the molecule into a geometry
that optimizes binding to AR. Modeling studies suggest a steric clash between
the bicyclic portion of 3 and the T877 residue in wt AR, thus preventing it from
being accommodated in an agonist conformation.
Structure-activity relationship (SAR) trends around the aniline moiety of 1
established that electron-withdrawing groups at the 4 0 -position had the greatest
impact on binding to AR, with an additive effect observed for an additional
electron-withdrawing substituent at the 3 0 -position. Both the bicyclic portion as
well as the aniline appeared to contribute to the observed agonist/antagonist
profile in MDA-MB-453 (wt AR) or LNCaP (T877A AR) cells. Despite sig-
nificant advances in in vitro potency, this series was eventually de-emphasized
since lead compounds exhibited unsatisfactory PK properties related to rapid
clearance and poor oral bioavailability. 12

6.3 Advanced Preclinical Leads

6.3.1 Identification of BMS-949
Introduction of an oxygen atom in the bicyclic portion of the first lead series 1
generated novel oxabicyclo[2.2.1] imides (Figure 6.2) that showed significant
improvement in oral absorption, 12 in addition to potent binding to the AR
(Table 6.1). Attempts to replace the 4-nitronaphthyl group in 4 led to 5 with a
significant drop in AR binding, but improved overall functional antagonist
activity. Modeling studies noted the presence of two methionine residues (M780
and M895) in the AR LBD adjacent to the C4 and C7 positions of the